Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that initially manifests itself in the striatum. How intrastriatal circuitry is altered by the disease is poorly understood. To help fill this gap, the circuitry linking spiny projection neurons (SPNs) to cholinergic interneurons (ChIs) was examined using electrophysiological and optogenetic approaches in ex vivo brain slices from wildtype mice and zQ175+/− models of HD. These studies revealed a severalfold enhancement of GABAergic inhibition of ChIs mediated by collaterals of indirect pathway SPNs (iSPNs), but not direct pathway SPNs (dSPNs). This cell-specific alteration in synaptic transmission appeared in parallel with the emergence of motor symptoms in the zQ175+/− model. The adaptation had a presynaptic locus, as it was accompanied by a reduction in paired-pulse ratio but not in the postsynaptic response to GABA. The alterations in striatal GABAergic signaling disrupted spontaneous ChI activity, potentially contributing to the network dysfunction underlying the hyperkinetic phase of HD.

中文翻译：

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亨廷顿病 zQ175+/- 小鼠模型中胆碱能中间神经元的 GABA 能抑制作用增强

亨廷顿舞蹈症 (HD) 是一种常染色体显性神经退行性疾病，最初表现为纹状体。人们对这种疾病如何改变纹状体内回路知之甚少。为了帮助填补这一空白，使用电生理学和光遗传学方法在野生型小鼠的离体脑切片和 zQ175 +/- 模型中检查了将多刺投射神经元 (SPN) 与胆碱能中间神经元 (ChIs) 连接起来的电路。这些研究揭示了由间接途径 SPN (iSPN) 而不是直接途径 SPN (dSPN) 的侧枝介导的 GABA 能抑制 Chis 的数倍增强。这种突触传递的细胞特异性改变与 zQ175+/- 模型中运动症状的出现同时出现。适应有一个突触前位点，因为它伴随着配对脉冲比的降低，但不是对 GABA 的突触后反应。纹状体 GABA 能信号的改变破坏了自发性 ChI 活动，可能导致 HD 多动期潜在的网络功能障碍。